Chronic myeloid leukemia | CML || Pathology (In English )

Summary

This video delves into Chronic Myeloid Leukemia (CML), a myeloid neoplasm characterized by the excessive proliferation of myeloid lineage precursors. It covers the introduction, pathogenesis involving the Philadelphia chromosome due to a translocation between chromosomes 9 and 22, and the BCR-ABL gene fusion leading to constitutive tyrosine kinase activity. The video also discusses the morphology, including hypercellular bone marrow and leukocytosis, and clinical features like splenomegaly and fatigue. It highlights the progression from chronic phase to accelerated phase and blast crisis, resembling acute leukemia.

Takeaways

• 🌟 Chronic Myeloid Leukemia (CML) is characterized by the excessive proliferation of myeloid lineage precursors, particularly granulocytic and megakaryocytic cells.
• 🧬 The pathogenesis of CML involves a translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia chromosome, which carries the BCR-ABL fusion gene.
• 🔬 The BCR-ABL gene encodes a protein with constitutive tyrosine kinase activity, leading to the activation of growth signaling pathways and growth factor-independent proliferation.
• 📈 CML progresses slowly but can accelerate over time, leading to an accelerated phase characterized by worsening anemia and thrombocytopenia.
• 🔍 The accelerated phase may progress to blast crisis, where the blood and bone marrow resemble acute leukemia with a blast count exceeding 20%.
• 🩸 Morphologically, CML is marked by hypercellular bone marrow, the presence of sea blue histocytes, and leukocytosis with increased granulocytes.
• 📊 Patients with CML often present with massive splenomegaly due to extensive extramedullary hematopoiesis, which is a key differentiating feature from other diseases.
• 👨‍⚕️ Clinical features of CML include anemia, weakness, fatigue, and splenomegaly, with the latter presenting as a dragging sensation in the abdomen.
• 📈 The natural history of CML involves a slow progression, but if untreated, it can lead to more severe symptoms and potentially blast crisis.
• 💡 The differentiation between CML and other diseases like AML or CLL can be aided by the presence of massive splenomegaly, a characteristic finding in CML.

Q & A

What is chronic myeloid leukemia (CML)?

CML is a condition characterized by the excessive proliferation of myeloid lineage precursors over a long period of time. It is a chronic condition involving the overproduction of granulocytic and megakaryocytic precursors.

What is the Philadelphia chromosome and how is it related to CML?

The Philadelphia chromosome is a result of a translocation between chromosome 9 and chromosome 22. This translocation leads to the fusion of the ABL gene from chromosome 9 and the BCR gene from chromosome 22, creating the BCR-ABL gene. This gene encodes for a BCR-ABL protein that has constitutive tyrosine kinase activity, leading to the pathogenesis of CML.

How does the BCR-ABL protein contribute to the development of CML?

The BCR-ABL protein, resulting from the fusion of BCR and ABL genes, has a tendency to self-dimerize, which activates the ABL part's tyrosine kinase activity. This leads to the continuous phosphorylation of other proteins, activating growth signaling pathways and resulting in growth factor-independent proliferation of granulocytic and megakaryocytic precursors, characteristic of CML.

What are the clinical features observed in patients with CML?

Patients with CML typically present with symptoms such as anemia, weakness, fatigue, anorexia, and weight loss. A characteristic finding is splenomegaly, which can cause a dragging sensation in the abdomen.

What is the natural progression of CML if left untreated?

If CML is left untreated, it progresses slowly over a course of time, typically around three years, to an accelerated phase. This phase is characterized by worsening clinical features like anemia and thrombocytopenia. If the patient develops additional cytogenetic abnormalities, it can progress to a blast crisis, resembling acute leukemia.

What is the significance of the blast crisis in CML?

The blast crisis in CML signifies a phase where the disease resembles acute leukemia, with blast cells (either myeloid or lymphoid) making up more than 20% of the cells in the blood and bone marrow. This indicates a severe stage of the disease and a poorer prognosis.

What is the role of extramedullary hematopoiesis in the development of splenomegaly in CML?

In CML, the bone marrow becomes hypercellular due to excessive proliferation of myeloid precursors, leading to a displacement of normal hematopoiesis to extramedullary sites like the spleen. This extensive extramedullary hematopoiesis results in massive splenomegaly, a characteristic finding in CML.

How does the morphology of the bone marrow change in CML?

In CML, the bone marrow biopsy reveals a hypercellular condition due to the excessive proliferation of granulocytic and megakaryocytic precursors. Additionally, sea blue histocytes, which are macrophages containing wrinkled, green-blue cytoplasm, are also observed.

What is the significance of the leukocytosis seen in the blood of CML patients?

Leukocytosis, or an increased white blood cell count, is observed in CML patients due to the excessive proliferation of granulocytic precursors. This leads to an increase in neutrophils, eosinophils, basophils, myelocytes, and metamyelocytes.

What are the implications of the massive splenomegaly seen in CML patients?

Massive splenomegaly in CML patients can cause a dragging sensation in the abdomen and may lead to splenic infarction. It is a significant finding that helps differentiate CML from other hematological conditions.

Outlines

00:00

🧬 Introduction to Chronic Myeloid Leukemia (CML)

This paragraph introduces Chronic Myeloid Leukemia (CML), a myeloid neoplasm characterized by the excessive proliferation of myeloid lineage precursors, particularly granulocytic and megakaryocytic cells. It explains that CML is a chronic condition that progresses over time and is marked by the formation of the Philadelphia chromosome due to a translocation between chromosomes 9 and 22. This translocation results in the fusion of the BCR and ABL genes, leading to the production of a BCR-ABL protein with constitutive tyrosine kinase activity. This abnormal protein activation triggers growth signaling pathways, leading to growth factor-independent proliferation, which is a hallmark of CML. The paragraph also outlines the natural progression of CML, which can lead to an accelerated phase and eventually a blast crisis, resembling acute leukemia.

05:03

🔬 Morphology and Clinical Features of CML

The second paragraph delves into the morphological aspects of CML, highlighting the hypercellular condition observed in bone marrow biopsies due to the overproliferation of granulocytic and megakaryocytic precursors. It mentions the presence of sea blue histocytes, which are macrophages with wrinkled, green-blue cytoplasm. The paragraph also discusses the clinical features of CML, including leukocytosis with an increased white blood cell count, often exceeding 100,000 cells per cubic millimeter, and the characteristic massive splenomegaly. This enlargement of the spleen is attributed to extensive extramedullary hematopoiesis, as the bone marrow is filled with abnormal cells. The clinical presentation of CML typically includes symptoms like anemia, weakness, fatigue, and a dragging sensation in the abdomen due to splenomegaly. The paragraph concludes by noting that as CML progresses, these symptoms can worsen, especially during the accelerated phase and blast crisis.

10:05

📢 Conclusion and Engagement Call

The final paragraph serves as a conclusion and a call to action for viewers. It encourages viewers to like the video and share it with friends. The speaker also invites viewers to reach out on Instagram for notes or more videos on the topic, with a link provided in the video description. This paragraph acts as a bridge between the educational content and the viewer, fostering engagement and interaction.

Keywords

💡Chronic Myeloid Leukemia (CML)

Chronic Myeloid Leukemia (CML) is a type of cancer that affects the blood and bone marrow. It is characterized by the excessive proliferation of myeloid lineage cells, particularly granulocytic and megakaryocytic precursors. In the video, CML is described as a chronic condition that progresses slowly over time, leading to the overproduction of white blood cells. The video script discusses the natural history of CML, including its progression to accelerated phases and blast crisis, which resembles acute leukemia.

💡Myeloid Lineage

Myeloid lineage refers to the developmental pathway of blood cells that give rise to various types of white blood cells, including neutrophils, eosinophils, basophils, monocytes, and platelets. The video emphasizes the excessive proliferation of granulocytic precursors in CML, which are part of the myeloid lineage. This overproduction leads to the characteristic high white blood cell counts seen in CML patients.

💡Philadelphia Chromosome

The Philadelphia Chromosome is a genetic abnormality that results from a translocation between chromosomes 9 and 22. This translocation leads to the fusion of the ABL gene from chromosome 9 with the BCR gene from chromosome 22, creating the BCR-ABL fusion gene. The video explains that this fusion gene is a hallmark of CML and is responsible for the uncontrolled proliferation of myeloid cells seen in the disease.

💡Blast Crisis

Blast crisis is a phase of CML characterized by a sudden increase in immature blood cells, or blasts, in the bone marrow and blood. The video describes how CML can progress to blast crisis, where the blast count exceeds 20%, resembling acute leukemia. This phase can be either myeloid or lymphoid, indicating the pluripotent nature of the cells affected in CML.

💡Morphology

Morphology in the context of the video refers to the study of the form and structure of cells, particularly as seen in bone marrow biopsies and blood examinations. The video discusses the hypercellular condition observed in the bone marrow of CML patients, as well as the presence of sea blue histocytes and the increase in various types of white blood cells in the blood.

💡Granulocytic Precursors

Granulocytic precursors are immature cells that develop into granulocytes, a type of white blood cell that includes neutrophils, eosinophils, and basophils. The video script highlights the excessive proliferation of granulocytic precursors in CML, which contributes to the elevated white blood cell counts and the development of characteristic symptoms.

💡Mega Karyocytic Precursors

Mega karyocytic precursors are cells that develop into megakaryocytes, which are responsible for platelet production. The video explains that, in CML, there is also an excessive proliferation of these precursors, leading to an increase in platelet count and contributing to the disease's pathology.

💡Extramedullary Hematopoiesis

Extramedullary hematopoiesis refers to the production of blood cells outside the bone marrow, typically in the spleen or liver. The video describes how, in CML, the bone marrow becomes hypercellular, leading to a displacement of normal hematopoiesis to the spleen and resulting in massive splenomegaly, a characteristic finding in CML patients.

💡Splenomegaly

Splenomegaly is the enlargement of the spleen, which is a common clinical feature in CML patients. The video script explains that massive splenomegaly can occur due to extensive extramedullary hematopoiesis, causing the spleen to expand as it takes on the role of blood cell production. This condition can lead to a dragging sensation in the abdomen and is a key differentiator of CML from other diseases.

💡Tyrosine Kinase Activity

Tyrosine kinase activity is a type of enzymatic action where a tyrosine kinase enzyme transfers a phosphate group from ATP to a tyrosine residue in a protein. In the context of the video, the BCR-ABL fusion protein, resulting from the Philadelphia chromosome, has constitutive tyrosine kinase activity, leading to the uncontrolled proliferation of cells characteristic of CML.

Highlights

Introduction to Chronic Myeloid Leukemia (CML) as a chronic condition characterized by the excessive proliferation of myeloid lineage precursors.

CML involves the granulocytic and megakaryocytic precursors, leading to the formation of granulocytes and platelets.

Pathogenesis of CML includes a translocation between chromosome 9 and 22, resulting in the Philadelphia chromosome.

The BCR-ABL gene fusion encodes a BCR-ABL protein with constitutive tyrosine kinase activity, leading to the activation of growth signaling pathways.

Growth factor independent proliferation is a hallmark of CML, affecting granulocytic and megakaryocytic precursors.

Natural history of CML includes a slow progression to an accelerated phase within three years without treatment.

Cytogenetic abnormalities in the accelerated phase of CML can lead to blast crisis, resembling acute leukemia.

Morphology of CML reveals hypercellular bone marrow with excessive proliferation of granulocytic and megakaryocytic precursors.

Sea blue histocytes, indicative of macrophages with wrinkled green-blue cytoplasm, are observed in CML bone marrow biopsies.

Leukocytosis, with a WBC count exceeding 100,000 cells per cubic millimeter, is a common blood examination finding in CML patients.

Massive splenomegaly is a characteristic clinical feature of CML due to extensive extramedullary hematopoiesis.

Clinical features of CML include anemia, weakness, fatigue, anorexia, weight loss, and splenomegaly.

In the accelerated phase of CML, symptoms like anemia and thrombocytopenia worsen significantly.

Blast crisis in CML is characterized by an increase in myeloblasts or lymphoblasts to more than 20 percent, resembling acute leukemia.

CML can progress to either myeloid or lymphoid blast crisis, indicating its origin from pluripotent cells with both myeloid and lymphoid potential.

Transcripts

foreign

leukemia or CML we have already

discussed many topics of myelody myeloid

neoplasm and lymphoid neoplasm this is

the another very topic of myeloid

neoplasm that is chronic myelody

leukemia we will be covering this video

under following subheadings in which we

will be firstly covering the

introduction on CML then we will be

covering pathogenesis on CML then we

will be covering morphology on CML and

then we will be covering the clinical

features that we see in the patients of

CML so firstly coming to the

introduction of CML see CML is a

condition in which we see the excessive

proliferation of precursors in Mito

lineage over a long period of time we

know as the name suggests this is a

chronic myeloid leukemia so this is a

chronic condition so the condition will

be seen in over a long period of time

and it is actually the myeloid leukemia

means what you will be seeing is the

excessive proliferation of precursors in

myeloid lineage cells so the cells would

be of myelody lineage the precursors of

myelody line is to be precise and what

the precursors of myelody lineage are

affected mostly are the granulocytic

precursors and mega karyocytic

precursors we have already seen the

normal hematopoiesis in normal

hematospoiesis we have seen this is the

myeloid lineage and in this myeloid

lineage the granular sites are formed by

the granulocytic precursors and the mega

karyocytes that is platelets are formed

from the mega karyocytic precursors

so in the condition of AML what develops

is the excessive proliferation of the

precursors of granulocyte and excessive

proliferation of precursors of the mega

karyocytes this is seen in the patients

of CML now what we will be discussing is

the detailed discussion on the

pathogenesis of CML

foreign

what happens in the patients of CML is

there is a translocation between the

chromosome number nine and chromosome

number 22.

there is a gene that is abl Gene which

is located from chromosome number nine

and a BCR Gene which is located on

chromosome number 22. what happens after

translocation is that chromosome number

22 gets both two genes that is BCR and

able gabl Gene and now this chromosome

number 22 this newly formed chromosome

number 22 is known as Philadelphia

chromosome so this Philadelphia

chromosome is formed after the

translocation between chromosome number

nine and chromosome number 22. this PCR

abl Gene encodes A protein that is BCR

abl protein

actually there are two parts of this

protein one is the BCR part and second

is the abl part the property of this BCR

part is that it it is the dimerization

moiety so it has a tendency of

self-dimerizing and abl part

this abl part it have a ability to

perform tyrosine kinase activity that is

constitutive tyrosine kinase activity so

these two parts perform their functions

independently so what happens that this

BCA part BCR part do the

self-dimerization and because of this

self-timerization the abl part gets

activated and it does perform the

constitutive kinase activity that is it

continuously phosphorylates other

protein substrates

this leads to the activation of certain

growth signaling Pathways such as

raspathway Jack stat pathway or ekiti

pathway which further leads to the

growth factor independent proliferation

now the growth factor independent

proliferation is generally seen in the

precursors of granulocytic precursors

and mega charismatic precursors in these

cells this growth factor independent

proliferation is generally seen and this

leads to the condition that is chronic

myeloid leukemia

now what happens in the CML

is that when CML progresses As Natural

History of disease it is a slow

progression because it is a chronic

condition but when it progresses without

any treatment over a course of time of

three years then what we see that CML

extends to The Accelerated phase what

happens in The Accelerated phase the

clinical features of the CML like anemia

and thrombocytopenia it goes worsen in

the accelerated phase and when this

patient of CML in accelerated phase is

predisposed with certain cytologic

abnormalities cytogenic abnormalities

like duplication of Philadelphia

chromosome like Trisomy of chromosome

number eight or isochromosome 17 Q then

this accelerated phase of CML progresses

to the condition of blast crisis now

what we see the now when we see the

blood and bone marrow of the patient it

resembles the acute leukemia because

there is a blast crisis blast these

blast crisis actually what does it means

is that the blast count is more than 20

percent in these patients it could be

myeloid blast it could be lymphoid blast

so it could be maloid blast crisis or

lymphoid blast crisis it actually

resembles acute leukemia we know that in

acute leukemia there is more than 20

blast seen in the blood and bone marrow

so here in the patient of CML when it

progresses to blast crisis it also

resembles acute leukemia and because we

are seeing here that it could be myeloid

blast crisis or lymphoid glass blast

crisis it is the evidence that the CML

originates from the pluripotent cells of

both myelody and lymphoid potential

because here we are seeing that it can

progress to either myeloid blast crisis

or lymphoid blast crisis

so this was the pathogenesis of CML now

what we will be discussing is the

morphology of CML

[Music]

now coming to the morphology of CML what

we see in the morphology is firstly what

we do when we do the bone marrow biopsy

we see that in the bone marrow biopsy

there is a hyper cellular condition that

we can appreciate in the patients of CML

hypercellular condition is seen actually

due to the excessive proliferation which

is seen in the granulocytic precursor

and make a karyocytic precursor cells so

there is a development of hypercellular

condition in a bone marrow what we see

also is the sea blue histocytes sea blue

histocytes are nothing these are

actually the scattered macrophages which

are seen and these macrophages actually

contain the Abundant amount of wrinkled

green blue cytoplasm so there are many

his sea blue histocytes that we can see

in the bone marrow of a patient of CML

now when we do the blood examination

what we see that in blood there is a

condition of leukocytosis that is

developed in the patients of CML the WBC

count is Inc is increased in the

patience of CML which exceeds more than

100 000 cells per millimeter Cube

the cells such as neutrophils

eosinophils basophils myocytes and

metamalocytes are mainly increased in

the patients of CML why are these cells

increased because this is a condition

where there is an excessive

proliferation of granulocytic precursors

when granulocytic precursors increases

so obviously the granulocytes will also

increase that is neutrophils eosinophil

basophil will increase and their

precursors like myelocytes and

metamalocytes will also increase in the

CML patients

now the next thing that we see in the

patient of CML is massive splenomegaly

it is a characteristic finding that we

see in the patient of CML so massive

splenomegaly some amount of hepatomegaly

and some amount of lymphadenopathy are

the things that we see in the patient of

CML why is this condition of massive

splinomegaly developing in the patient

of CML the reason is there is an

extensive extramedillary hepatopoiesis

in the patients of CML that leads to the

massive splenomegaly why there is

extensive extra medullar hematopoiesis

because the normal bone marrow is filled

with hypercellular condition and these

cells are nothing but only the

granulocytic and megakaryocetic

precursors so when the bone marrow is

filled with these type of precursors the

normal hematopoiesis could not carry out

when normal hematopoiesis does not occur

uh optimally then what happens that

there is a need of extra medullary

hematopoiesis and when this need is very

extensive when there is an extensive

extramedillary hepatopoiesis from the

spleen the spleen size increases and

there is a condition of massive

splenomegaly which is seen in the

patients of CML

so this is a finding which is helpful

for differentiating the CML from other

diseases like AML Al or CLL so we can

differentiate this CML from other

diseases on the basis of only this

splinomegaly the patient of CML usually

presents with dragging sensation in

abdomen because of this massive

splenomegaly so this is a characteristic

finding what we see in the patient of

CML after this we will be discussing the

clinical features that will be seen in

the patient of CML

now the clinical features that we see in

the patients of CML the CMS the patient

of CML is generally of adult age Europe

and because it is a chronic myeloid

leukemia it is a chronic condition the

onset of the diseases in really

Insidious what we see as a clinical

features is anemia weakness fatigue in

the patient's anorexia and weight loss

in the patient and the characteristic

finding is splenomegaly what we see in

the patient of CML so splenomegaly how

can we appreciate that the patient is a

patient of splenomegaly there is a

dragging sensation in the abdomen which

is seen in the patient of CML and this

refers that the patient is is suffering

from splenomegaly and we can also

appreciate some type of splenic in fact

in the patients of CML so this

splenomegaly is to such extent that it

can lead to the splinic in fact

now when the CML is in a stage of

natural history of disease there is a

slow progression of the disease then

these symptoms are mostly prominent but

when the disease progresses to The

Accelerated phase the anemia and

thrombocytopenia worsens and it is

increased to very much extent when the

patient comes to the blast crisis phase

then this is a condition in which

myeloblast or lymphoblast are increased

more than 20 percent and it is the case

that resembles the acute leukemia so

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